Oncotarget

Research Papers:

Differentiation status of primary chronic myeloid leukemia cells affects sensitivity to BCR-ABL1 inhibitors

Paavo O. Pietarinen, Christopher A. Eide, Pilar Ayuda-Durán, Swapnil Potdar, Heikki Kuusanmäki, Emma I. Andersson, John P. Mpindi, Tea Pemovska, Mika Kontro, Caroline A. Heckman, Olli Kallioniemi, Krister Wennerberg, Henrik Hjorth-Hansen, Brian J. Druker, Jorrit M. Enserink, Jeffrey W. Tyner, Satu Mustjoki and Kimmo Porkka _

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Oncotarget. 2017; 8:22606-22615. https://doi.org/10.18632/oncotarget.15146

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Abstract

Paavo O. Pietarinen1, Christopher A. Eide2,3, Pilar Ayuda-Durán4, Swapnil Potdar5, Heikki Kuusanmäki5, Emma I. Andersson1, John P. Mpindi5, Tea Pemovska5,6, Mika Kontro1, Caroline A. Heckman5, Olli Kallioniemi5, Krister Wennerberg5, Henrik Hjorth-Hansen7,8, Brian J. Druker2,3, Jorrit M. Enserink4, Jeffrey W. Tyner2,9, Satu Mustjoki1,10,*, Kimmo Porkka1,*

1Hematology Research Unit Helsinki, University of Helsinki and Department of Hematology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland

2Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA

3Howard Hughes Medical Institute, Portland, OR, USA

4Oslo University Hospital, University of Oslo, Oslo, Norway

5Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland

6Research Center for Molecular Medicine (CeMM) of the Austrian Academy of Sciences, Vienna, Austria

7Department of Hematology, St Olavs Hospital, Trondheim, Norway

8Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway

9Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, OR, USA

10Department of Clinical Chemistry, University of Helsinki, Helsinki, Finland

*These authors contributed equally to this work

Correspondence to:

Kimmo Porkka, email: Kimmo.porkka@helsinki.fi

Keywords: chronic myeloid leukemia, high-throughput drug screening, ex vivo, tyrosine kinase inhibitors, CD34

Received: September 20, 2016     Accepted: January 24, 2017     Published: February 07, 2017

ABSTRACT

Tyrosine kinase inhibitors (TKI) are the mainstay treatment of BCR-ABL1-positive leukemia and virtually all patients with chronic myeloid leukemia in chronic phase (CP CML) respond to TKI therapy. However, there is limited information on the cellular mechanisms of response and particularly on the effect of cell differentiation state to TKI sensitivity in vivo and ex vivo/in vitro. We used multiple, independent high-throughput drug sensitivity and resistance testing platforms that collectively evaluated 295 oncology compounds to characterize ex vivo drug response profiles of primary cells freshly collected from newly-diagnosed patients with BCR-ABL1-positive leukemia (n = 40) and healthy controls (n = 12). In contrast to the highly TKI-sensitive cells from blast phase CML and Philadelphia chromosome-positive acute lymphoblastic leukemia, primary CP CML cells were insensitive to TKI therapy ex vivo. Despite maintaining potent BCR-ABL1 inhibitory activity, ex vivo viability of cells was unaffected by TKIs. These findings were validated in two independent patient cohorts and analysis platforms. All CP CML patients under study responded to TKI therapy in vivo. When CP CML cells were sorted based on CD34 expression, the CD34-positive progenitor cells showed good sensitivity to TKIs, whereas the more mature CD34-negative cells were markedly less sensitive. Thus in CP CML, TKIs predominantly target the progenitor cell population while the differentiated leukemic cells (mostly cells from granulocytic series) are insensitive to BCR-ABL1 inhibition. These findings have implications for drug discovery in CP CML and indicate a fundamental biological difference between CP CML and advanced forms of BCR-ABL1-positive leukemia.


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